Continuing Z01AG00905-04 LCI, we received an Investigators' IND from the FDA to study exendin-4 in diabetic humans. In December 1998, we started an acute study of exendin-4 (RPN:GRC98-10-26-01 in non-diabetic (n=12) and diabetic (n=12) subjects to see if it was (1) insulinotropic, (2) long-lived, (3) more potent than GLP-1, (4) effective in the diabetic state, and (5)effective in controlling post-prandial glucose elevations (which are a major problem in type 2 diabetes due to deficient first phase insulin secretion). We found all five aspects to be the case. We also found that exendin-4 was insulinomimetic (increases glucose uptake) in both non-diabetic and diabetic humans. This confirms what we suspected as outlined in Z01AG00906-04 LCI in which we hypothesized GLP-1 was insulinomimetic. Using the more potent exendin-4, we could clearly elucidate this finding. Subsequently, we initiated two more clinical studies(RPN: GRC99-02-09-01 and GRC99-07-07-01). We gave exendin-4 daily subcutaneously to type 2 diabetic subjects for up to one month, with measures of insulin secretion and glucose uptake monitored before and after the 30-day treatment. In order to prove that exendin-4 is a true insulinomimetic agent, we will carry out an acute study of exendin-4 in type 1 diabetic subjects. As they have no endogenous insulin secretion, any effect we see on glucose uptake should be due to the administration of exendin-4 and not due to endogenous insulin secretion. We think that exendin-4, or one of its analogs which we are developing, will be a future treatment for diabetes. We are also hoping that exendin-4 may be used in a transdermal fashion to eliminate the need for subcutaneous injection.